Table of Contents

Background and Key Questions

Although oral antidiabetic agents are used
as first-line agents in patients with type 2
diabetes, insulin is required in a significant
number of patients at some stage during
the management of diabetes to maintain
optimal glycemic control. Insulin use has
been suggested as a first-line therapy in
patients with type 2 diabetes, either as an
add-on therapy to the existing noninsulin
antidiabetic medications or as a
replacement for noninsulin medications.
According to the National Health Interview
Survey, 28 percent of patients with type 2
diabetes are using insulin either alone (16
percent) or in combination with oral
antidiabetic agents (12 percent).

To mimic the release of insulin from
pancreatic beta-cells in response to food
intake, near-physiologic insulin
replacement regimens involve giving
insulin at specific times in relation to
meals. In addition, some formulation of a
longer acting insulin is prescribed to mimic
the relatively constant and slow release of
insulin that regulates hepatic
gluconeogenesis and lipolysis. However,
the addition of insulin to treatment regimens may result in decreased flexibility in the
timing of meals and activities, increased frequency of
blood glucose monitoring, and an increased risk of
weight gain and hypoglycemia. Also, the requirement
for multiple injections of short-acting insulin (bolus
insulin) and long-acting insulin (basal insulin) may
affect patients' overall satisfaction with their treatment
regimen.

Premixed insulin preparations are a therapeutic
alternative to multiple insulin injections in a nearphysiologic
regimen that is also convenient for patients.
A number of patient-related factors have been
identified that may help physicians to select patients for
therapy with premixed insulin preparations. Such
preparations are generally appropriate for patients who:
(1) desire a convenient and simple insulin regimen; (2)
are unwilling to administer multiple daily injections or
use an insulin pump; (3) are unwilling to or cannot
undertake carbohydrate counting; (4) have a relatively
predictable (routine) life style; and (5) consume meals
with approximately the same composition of calories,
carbohydrates, fats, and fiber at fairly consistent and
reproducible times every day.

Insulin analogues have been developed by altering one
of the two polypeptide chains of human insulin. This
modification changes the pharmacokinetic and
pharmacodynamic properties of the insulin, imparting
the desired rapidity or duration of action. Premixed
insulin analogues are derived from rapid-acting insulin
analogues and consist of a mixture of rapid-acting
insulin analogues and an intermediate-acting protamine
suspension or protamine alone.

In the management of type 2 diabetes, the place of
premixed insulin analogues in relation to other insulin
regimens and noninsulin antidiabetic agents is as yet
unclear.When compared with premixed human insulin,
premixed insulin analogues may provide a glucoselowering
profile that more closely mimics the
physiology of a person without diabetes, thus providing
better glycemic control. In addition, compared with
premixed human insulin preparations, premixed insulin
analogues allow patients more flexibility in timing their
meals, since premixed insulin analogues can be
administered within 15 minutes of a meal.

Despite their advantages, the effect of premixed insulin
analogues on fasting and postprandial glucose and
hemoglobin A1C (A1c) compared with the effect of
other antidiabetic medications has not been clearly
established. Although several studies have demonstrated
that insulin aspart 70/30 and insulin lispro 75/25 are
more effective in lowering postprandial glucose levels
than neutral protamine Hagedorn (NPH)/regular 70/30,
their effectiveness in lowering A1c appears similar.
Similarly, these same two premixed insulin analogues
appear to be more effective in lowering postprandial
glucose but less effective in lowering fasting glucose
than the long-acting insulin analogues are. Moreover,
several studies have found that while the rate of side
effects (such as hypoglycemia) is similar for premixed
insulin analogues and premixed human insulin
preparations, these side effects are less common with
the long-acting insulin analogues than with premixed
insulin analogues.

Given the increasing prevalence of type 2 diabetes, the
large number of patients who use insulin for glycemic
control, and the well-documented importance of
glycemic control in decreasing mortality and preventing
long-term complications, it is important to review and
evaluate the weight of evidence for the safety and
effectiveness of these insulin therapies relative to
alternative insulin and noninsulin antidiabetic regimens.

To date, no one study has compared premixed insulin
analogues with other insulin and noninsulin antidiabetic
agents in terms of reducing fasting and postprandial
glucose, A1c, microvascular and macrovascular diabetic
complications and in terms of the side effects of
treatment. Clinicians may be better able to choose the
most effective therapy for their patients with diabetes if
they have the results of an objective, impartial,
comprehensive evidence-based review of the
comparative effectiveness and safety of different
therapeutic options for the treatment of type 2 diabetes.
We have therefore performed a systematic review of
published studies dealing with the comparative
effectiveness and safety of all premixed insulin
analogues that are approved by the U.S. Food and Drug
Administration (FDA) and available in the United
States.

For adults with type 2 diabetes, do premixed
insulin analogues differ from other commonly
used insulin preparations with regard to safety,
adverse effects, or adherence? The adverse effects
of interest include, but are not limited to,
hypoglycemia (nocturnal and daytime), weight
gain, and interactions with other medications.

Does the effectiveness or safety of the new
premixed insulin analogue regimens vary across
the following subpopulations of patients with type
2 diabetes?

The elderly (≥ 65 years), very elderly (≥ 85
years).

Other demographic groups (ethnic or racial
groups, genders).

Individuals with comorbid medical
conditions.

Individuals with limited life expectancy.

Individuals with disabilities.

What are the effectiveness and safety of the new
premixed insulin analogue regimens in individuals
on oral antidiabetic agents and individuals with
different blood glucose patterns (such as fasting
hyperglycemia or postprandial hyperglycemia) or
types of control (such as tight control, usual
control, good fasting, or postprandial control)?

While effective in lowering postprandial glucose and
A1c, premixed analogues increased the incidence of
hypoglycemia and were associated with weight gain to
a greater extent than the long-acting insulin analogues
were. Use of insulin aspart 70/30 in randomized
controlled trials was associated with a higher incidence
of overall and minor hypoglycemia. Similarly, weight
gain was significantly higher with insulin aspart 70/30
(pooled mean difference = 2.5 kg; 95-percent CI: 1.6 to
3.4 kg; p < 0.001). Although the incidence of
hypoglycemia was neither consistent nor statistically
significant across all trials, the direction of the
individual study effect sizes suggested that both insulin
lispro 75/25 and insulin lispro 50/50 may increase the
incidence of hypoglycemia when compared with longacting
insulin analogues. In two studies, use of insulin
lispro 50/50 resulted in a larger weight gain than longacting
insulin analogues did, although this effect
reached statistical significance in only one study. None
of the studies reported the comparative effects of
insulin lispro 75/25 and long-acting insulin analogues
on weight change.

We found two parallel-arm trials (one randomized and
one nonrandomized) that compared premixed insulin
analogues with a combined regimen of long-acting
insulin analogue (basal) and rapid-acting insulin
analogue (bolus). The randomized trial found that the
basal-bolus regimen was more effective than insulin
lispro 50/50 in lowering fasting glucose (147 versus
159 mg/dL; p = 0.013), 2-hour postbreakfast glucose
(155 versus 174 mg/dL; p = 0.002), and A1c (6.8
versus 6.9 percent; p = 0.02). The incidence of overall,
nocturnal, and severe hypoglycemia was similar for the
two treatments. The nonrandomized prospective trial
found that insulin aspart 70/30 was similar to the basalbolus
regimen in lowering fasting and postprandial
glucose levels but was more effective in lowering A1c
and was associated with fewer minor hypoglycemic
events. Both studies found no difference in weight
change between the two treatment regimens.

Premixed insulin analogues versus premixed human insulin

We found 16 studies that compared premixed insulin
analogues with premixed human insulin. Premixed
insulin analogues and premixed human insulin appeared
to be similarly effective in lowering fasting glucose.
Premixed insulin analogues were more effective in
lowering postprandial glucose. Premixed insulin
analogues appeared to be similar to premixed human
insulin in lowering A1c levels and the incidence of
hypoglycemia.

We found only one study that evaluated this
comparison. This study did not report on the changes in
fasting and postprandial glucose. Changes in A1c and
the incidence of severe hypoglycemia did not differ
between the two treatment regimens. The premixed
insulin analogue group experienced significantly more
weight gain.

Premixed insulin analogues versus intermediateacting
insulin

Only two studies evaluated this comparison. In one
parallel-arm randomized study enrolling 95 patients,
NPH was given daily at 10:00 P.M. and insulin aspart
70/30 was given once daily 10 minutes before dinner,
with metformin being continued in both arms. In the
second parallel-arm randomized study enrolling 403
patients, all oral antidiabetic agents were discontinued,
and insulin aspart 70/30 and NPH were given
immediately before breakfast and dinner. Both studies
reported similar results; premixed insulin analogues
were as effective as NPH (an intermediate-acting
insulin) in lowering fasting and postprandial glucose
levels and A1c, and were similar in terms of the
incidence of hypoglycemia and the frequency and
magnitude of the weight gain produced. These results
are in contrast to what would be expected on the basis
of the pharmacokinetic and pharmacodynamic
information available for the two agents and may reflect
the study design characteristics or a low power of the
studies to detect a difference.

Premixed insulin analogues versus noninsulin
antidiabetic agents

Ten studies evaluated this comparison. Premixed insulin
analogues were more effective than noninsulin
antidiabetic agents in terms of glycemic control
(lowering fasting glucose, postprandial glucose, and
A1c levels) but were also associated with an increased
risk of hypoglycemia and weight gain.

One study that compared a premixed insulin analogue
(insulin aspart 70/30) to exenatide found that insulin
aspart 70/30 was as effective as exenatide in lowering
fasting glucose levels but was less effective in lowering
postprandial glucose levels. There was no difference in
terms of lowering A1c levels. Patients on exenatide lost
weight, in contrast to the weight gain experienced by
patients on premixed insulin analogues. However, more
patients withdrew from the exenatide arm than from the
premixed insulin analogue arm of the study.

Premixed insulin analogues versus premixed insulin analogues

We found only three studies that compared one
premixed insulin analogue with another, and we saw no
difference among these premixed insulin analogues
(insulin aspart 70/30, insulin lispro 75/25, and insulin
lispro 50/50) in terms of lowering fasting or
postprandial glucose levels, A1c, or the incidence of
hypoglycemia, or in terms of weight change.

We found only 16 studies that evaluated clinical
outcomes such as mortality. No statistically significant
differences were found between premixed insulin
analogues and their comparators in terms of all-cause
mortality, cardiovascular mortality, or cardiovascular
morbidity.When premixed insulin analogues were
compared with other antidiabetic medications, a
suggestion of harm was seen in the pooled odds ratios
for all-cause mortality, cardiovascular mortality, and the
combined outcome of cardiovascular morbidity and
mortality, but these point estimates were based on few
absolute events in only a few studies, in which clinical
outcomes were not the primary end points. Insufficient
or no evidence was found with regard to microvascular
outcomes.

While the rosiglitazone and pioglitazone labels have
warnings concerning increased congestive heart failure
events in subjects who use insulin of any type in
conjunction with these oral medications (compared
with those who use insulin alone), we did not observe
any congestive heart failure events in the few available
studies, which reported few absolute events. In
addition, rosiglitazone labels have warnings regarding
the increased ischemic risk in patients who use
rosiglitazone with insulin, as compared with insulin
alone. The evidence was insufficient to allow us to
determine whether this risk applied to premixed insulin
analogues specifically. Until more data are available,
physicians should be aware of these warnings.

No evidence was found with regard to adherence. Six
studies evaluated quality of life. No firm conclusions
could be drawn because of the differences between
studies in terms of outcome definitions, measurement
techniques, populations, and comparators.

We found three studies that compared using premixed
insulin analogues alone with using a combination of a
premixed insulin analogue plus an oral antidiabetic
agent. These studies found that a combination of
premixed insulin analogue and oral antidiabetic agent
was probably more effective than a premixed analogue
alone in lowering fasting glucose levels (insufficient
data to be able to pool studies) and postprandial glucose
levels (pooled mean difference = -5.8 mg/dL, 95-
percent CI: -15.7 to 4.1 mg/dL; p = 0.25). However, a
combination of premixed insulin analogue plus oral
antidiabetic agent was more effective than monotherapy
with premixed insulin analogue in lowering A1c
(pooled mean difference = 0.37 percent; 95-percent CI:
0.12 to 0.62 percent; p = 0.004) without increasing the
incidence of minor hypoglycemia (OR = 0.84; 95-
percent CI: 0.45 to 1.56; p = 0.6) or symptom-only
hypoglycemia (OR = 1.1; 95-percent CI: 0.77 to 1.6; p
= 0.6). The effect on weight gain appeared to be related
to the type of oral antidiabetic agent used with the
premixed insulin analogue. In both studies in which
metformin was the oral agent in the combination
therapy, monotherapy with premixed insulin analogues
resulted in greater weight gain. In one study in which
pioglitazone was the oral agent in the combination
therapy, monotherapy with premixed analogues was
associated with less weight gain (4.0 versus 2.2 kg).

Effect of premixed insulin analogues in patients with
different intensities of glucose control

We did not find any study that compared intensive
glycemic control with standard glycemic control in
patients using premixed insulin analogues.

Applicability

All the identified studies were efficacy trials and not
effectiveness trials; thus, the ability to generalize their
findings to the U.S. population with diabetes as a whole
and to current clinical practice is clearly limited. In
general, the study populations reflected the age and sex
composition of the U.S. population with diabetes.

However, the spectrum of diabetic complications and
comorbidities seen in the enrolled participants was
limited. Some trials excluded insulin-naïve patients,
while others excluded all insulin-treated patients. All
trials either excluded patients with cardiac, renal, or
hepatic disease or did not report whether or not such
patients were included, thus limiting our ability to
generalize their results to these subpopulations.

Remaining Issues

Gaps in evidence and future directions for research are
outlined below.

There was only limited evidence to allow us to
compare premixed insulin analogues with a
regimen consisting of a long-acting insulin
analogue (basal insulin) plus a rapid-acting insulin
analogue (bolus insulin). Probably the most
important comparative study that needs to be
performed is to compare premixed insulin
analogues with a basal-bolus regimen.

All the studies identified were of very short
duration. Studies with a longer planned duration of
followup are needed to allow us to ascertain
whether the gains achieved early in treatment are
sustainable in the long term and whether
differences between the comparators appear later
during the treatment.

The lack of effectiveness studies limited our ability
to make generalizations from the reported results
to all patients with diabetes in the United States.
Studies designed to examine the effectiveness of
premixed insulin analogues should be conducted
with less restrictive inclusion criteria and in a
setting that more closely mimics the usual clinical
practice.

There were no, or only very limited, data
specifically related to the comparative
effectiveness of premixed insulin analogues and
other antidiabetic agents in certain subpopulations.
Patients with comorbid conditions, racial
minorities, and very elderly patients need to be
enrolled in studies examining the efficacy and
effectiveness of premixed insulin analogues in
these subpopulations.

Clinical outcomes need to be studied in order to
better evaluate the safety of premixed insulin
analogues, especially given the suggestion of
increased mortality and cardiovascular morbidity
seen in the pooled estimates from the available
short-duration trials. Studies need to be
sufficiently powered to make it possible to assess
clinical outcomes.

Because diabetes is a chronic disease that requires
different injection patterns and glucose testing
depending on the type of medication regimen
prescribed, evaluating patient adherence and
quality of life for users of premixed insulin
analogues compared with those on other diabetes
regimens is critical.

Table

1 While the rosiglitazone and pioglitazone labels have warnings concerning increased congestive heart failure events in subjects who use insulin of any type in conjunction with these oral medications (versus insulin alone), we did not observe any congestive heart failure events in these few studies, which reported only very few absolute events. In addition, rosiglitazone labels have warnings regarding increased ischemic risk in patients who use rosiglitazone with insulin compared to those who use insulin alone. There was insufficient evidence to allow us to determine whether this risk applies to premixed insulin analogues specifically. Until more data are available, physicians should be aware of these warnings.

Premixed insulin analogues are better than oral antidiabetic agents in lowering postprandial glucose, although there is no evidence available for insulin lispro 50/50.
There is not enough evidence to conclusively compare the new incretin mimetic agent exenatide to premixed insulin analogues in terms of lowering postprandial glucose.

Premixed insulin analogues

Low

The evidence was too weak to make a conclusion.

A1c

Long-acting insulin analogues

High

Premixed insulin analogues are more effective than long-acting insulin analogues in lowering A1c.

No studies evaluated other clinical outcomes, such as retinopathy and neuropathy.

Hypoglycemia

General

Many of the comparisons were made in too few studies to allow us to draw any conclusions.
The effect of premixed insulin analogues on the incidence of serious hypoglycemia cannot be conclusively addressed because of the very small numbers of serious hypoglycemic events reported in the studies.

Long-acting insulin analogues

Premixed insulin analogues are more likely to be associated with hypoglycemia than long-acting insulin analogues are.

There is not enough evidence to allow us to conclusively compare the weight change after treatment with premixed insulin analogues versus the change after treatment with other antidiabetic drugs, except as noted below.

There is no evidence for adherence in terms of the comparisons of interest.

Quality of life

Low

No significant difference was noted in the 3 studies that compared premixed insulin analogues with other antidiabetic agents and used a validated quality-of-life instrument.
No firm conclusions can be drawn regarding quality-of-life outcomes because of the differences between studies in outcome definitions, measurement techniques, populations, and comparators.

Effect of premixed insulin analogues in certain subpopulations

No evidence

We did not find any study that specifically explored the effect of premixed insulin analogues in specific subpopulations, such as the very elderly, those with comorbid conditions, or minorities.